Solubilized CoQ-10

ABSTRACT

The present invention is directed to compositions and methods of delivery of CoQ-10 solubilized in monoterpenes. Use of monoterpenes as dissolving agents, greatly effects the ability to incorporate greater amounts of bioactive CoQ-10 in formulations, such as soft gel capsules.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.14/560,136, filed Dec. 4, 2014, which is a continuation of U.S.application Ser. No. 14/165,319, filed Jan. 27, 2014, issued as U.S.Pat. No. 8,932,585, which is a continuation of U.S. application Ser. No.13/357,402, filed Jan. 24, 2012, issued as U.S. Pat. No. 8,658,161,which is a continuation of U.S. application Ser. No. 10/953,328, filedSep. 29, 2004, issued as U.S. Pat. No. 8,105,583, which is aContinuation-in-Part of U.S. application Ser. No. 10/674,268, filed Sep.29, 2003, issued as U.S. Pat. No. 8,124,072, the contents of which arehereby incorporated herein in their entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to the solubilization of coenzyme Q-10 andanalogs thereof in monoterpenes, thereby providing increasedbioavailability in delivery.

BACKGROUND OF THE INVENTION

CoQ-10 (coenzyme Q10) is a fat-soluble quinone that is structurallysimilar to vitamin K and commonly known as ubiquinone. CoQ-10 is foundin most living organisms, and is essential for the production ofcellular energy. CoQ-10 (2,3 dimethyl-5 methyl-6-decaprenylbenzoquinone) is an endogenous antioxidant found in small amounts inmeats and seafood. Although CoQ-10 is found in all human cells, thehighest concentrations of CoQ-10 occur in the heart, liver, kidneys, andpancreas. It is found naturally in the organs of many mammalian species.

CoQ-10 can be synthesized in the body or it can be derived from dietarysources. Situations may arise, however, when the need for CoQ-10surpasses the body's ability to synthesize it. CoQ-10 can be absorbed byoral supplementation as evidenced by significant increases in serumCoQ-10 levels after supplementation.

CoQ-10 is an important nutrient because it lies within the membrane of acell organelle called the mitochondria. Mitochondria are known as the“power house” of the cell because of their ability to produce cellularenergy, or ATP, by shuttling protons derived from nutrient breakdownthrough the process of aerobic (oxygen) metabolism. CoQ-10 also has asecondary role as an antioxidant. CoQ-10, due to the involvement in ATPsynthesis, affects the function of almost all cells in the body, makingit essential for the health of all human tissues and organs. CoQ-10particularly effects the cells that are the most metabolically active:heart, immune system, gingiva, and gastric mucosa

Several clinical trials have shown CoQ-10 to be effective in supportingblood pressure and cholesterol levels. Furthermore, CoQ-10 has also beenshown to improve cardiovascular health. CoQ-10 has been implicated asbeing an essential component in thwarting various diseases such ascertain types of cancers. These facts lead many to believe that CoQ-10supplementation is vital to an individual's well being.

CoQ-10 is sparingly soluble in most hydrophilic solvents such as water.Therefore, CoQ-10 is often administered in a powdered form, as in atablet or as a suspension. However, delivery of CoQ-10 by these methodslimits the bioavailability of the material to the individual.

There is a need in the art for an improved methodology to deliverincreased amount of bioavailable CoQ-10 to an individual in needthereof.

BRIEF SUMMARY OF THE INVENTION

The present invention pertains to the surprising discovery thatubiquinone (CoQ-10) and related analogs thereof can be readily dissolvedin varying concentrations in monoterpenes. Generally, until the presentdiscovery, most CoQ-10 liquid delivery methods could solubilize only upto about 5% by weight of the CoQ-10 in the “solvent”. Typical solventsincluded various oils or the CoQ-10 was held in suspension. The presentinvention provides the ability to solubilize CoQ-10 in monoterpenes inconcentrations of up to about 60% (weight to weight) without the need toaggressively heat the solution or with gentle warming. In particular,the solubilization of the CoQ-10 with monoterpenes can be accomplishedat ambient temperatures.

In one aspect, the present invention pertains to compositions thatinclude coenzyme Q-10 or an analog thereof with a sufficient quantity ofa monoterpene that is suitable to solubilize said coenzyme Q-10 and apharmaceutically acceptable carrier. Generally, about 30 to about 45% ofthe CoQ-10 (by weight) is solubilized in the monoterpene. In particular,the monoterpene is limonene. The compositions of the invention areuseful as dietary supplements or as nutriceuticals.

In particular, the compositions of the invention are included in a softgelatin (soft gel) capsule. Typically, the soft gelatin capsule includesat least 5% by weight of coenzyme Q-10 or an analog thereof solubilizedin a monoterpene. Typical monoterpenes include, for example, perillylalcohol, perillic acid, cis-dihydroperillic acid, trans-dihydroperillicacid, methyl esters of perillic acid, methyl esters of dihydroperillicacid, limonene-2-diol, uroterpenol, and combinations thereof.

In another embodiment, the present invention pertains to methods fordelivery of an effective amount of bioavailable CoQ-10 to an individual.The method includes providing CoQ-10 solubilized in a monoterpene, suchthat an effective amount of CoQ-10 is provided to the individual.

In still another embodiment, the present invention also includespackaged formulations of the invention that include a monoterpene as asolvent for the CoQ-10 and instructions for use of the tablet, capsule,elixir, etc.

In one aspect, the present invention provides solubilized coenzyme Q-10compositions that include coenzyme Q-10 or an analog thereof, asufficient quantity of a monoterpene suitable to solubilize saidcoenzyme Q-10 or analog thereof, and an acceptable carrier. Thecompositions provide a percentage of coenzyme Q-10 dosage that isabsorbed by an individual of between about 5 percent and about 12percent of said coenzyme Q-10 or analog thereof that is administered.The ranges of absorbed coenzyme Q-10 are from about 5 percent to about12 percent, from about 6 percent to about 10 percent, and from about 6.5percent to about 9.5 percent, based on the dosage of coenzyme Q-10 oranalog thereof taken.

In another aspect, the present invention provides solubilized coenzymeQ-10 compositions that include coenzyme Q-10 or an analog thereof, asufficient quantity of a monoterpene suitable to solubilize saidcoenzyme Q-10 or analog thereof, and an acceptable carrier. Thecompositions provide a bioavailable steady state plasma level ofcoenzyme Q-10 or an analog thereof of between about 2.5 μg/ml to about3.5 μg/ml. Suitable ranges of steady state plasma levels of coenzymeQ-10 or analog thereof are from about 2.5 μg/ml to about 3.5 μg/ml, fromabout 2.75 μg/ml to about 3.25 μg/ml and from about 2.75 μg/ml to about3.0 μg/ml, based on the dosage of coenzyme Q-10 or analog thereof taken.

In still yet another aspect, the present invention provides compositionsthat include solubilized coenzyme Q-10 or an analog thereof, asufficient quantity of a monoterpene suitable to solubilize saidcoenzyme Q-10 or analog thereof, and an acceptable carrier. Thecompositions provide a peak plasma level of coenzyme Q-10 or analogthereof of between about 2.1 μg/ml to about 3.0 μg/ml. Suitable rangesof peak plasma levels of coenzyme Q-10 or analog thereof are from about2.1 μg/ml to about 3.0 μg/ml, from about 2.2 μg/ml to about 2.8 μg/mland from about 2.2 μg/ml to about 2.5 μg/ml.

In another aspect, the present invention pertains to methods fordelivery of an effective amount of bioavailable CoQ-10 to an individual.The methods include providing CoQ-10 solubilized in a monoterpene, suchthat an effective amount of CoQ-10 is provided to the individual so thatthe dosage absorbed, the steady state plasma levels of coenzyme Q-10, orthe peak plasma levels of coenzyme Q-10 are sustained.

In still another embodiment, the present invention also includespackaged formulations of the invention that include a monoterpene as asolvent for the CoQ-10 and instructions for use of the tablet, capsule,elixir, etc. so that the dosage absorbed, the steady state plasma levelsof coenzyme Q-10, or the peak plasma levels of coenzyme Q-10 aresustained.

While multiple embodiments are disclosed, still other embodiments of thepresent invention will become apparent to those skilled in the art fromthe following detailed description, which shows and describesillustrative embodiments of the invention. As will be realized, theinvention is capable of modifications in various obvious aspects, allwithout departing from the spirit and scope of the present invention.Accordingly, the drawings and detailed description are to be regarded asillustrative in nature and not restrictive.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts individual single dose (60 mg) peak absorption curves forsolubilized coenzyme Q-10;

FIG. 2 shows individual daily dose (60 mg/day) steady state plasmacoenzyme Q-10 bioavailability curves for the solubilized coenzyme Q-10;

FIG. 3 provides a graphical representation of single dose peakabsorption curves for the solubilized coenzyme Q-10 (60 mg) (upper line,♦)(Example 5) formulation and Example 6 (30 mg) (lower line, ▪). TheCmax for both formulations occurred at 6 hours. The change in plasmacoenzyme Q-10 at Cmax was significantly greater for the solubilizedcoenzyme Q-10 by a three fold factor. The calculated percentage of doseabsorbed at Cmax was 7.95 percent for the solubilized coenzyme Q-10 ascompared to 6.04 percent for Example 6; and

FIG. 4 is a graphical representation of the steady state bioavailabilitycurves for the solubilized coenzyme Q-10 (upper line, ♦)(Example 5) andExample 6 (lower line, ▪) at a daily dose of 60 mg/day. Plasma levels at7, 14, 21 and 28 days were significant (P<0.01) for the solubilizedcoenzyme Q-10 formulation.

DETAILED DESCRIPTION

The present invention pertains to the surprising discovery thatubiquinone (CoQ-10) can be readily dissolved in varying concentrationsin monoterpenes. CoQ-10 is found in most living organisms, and isessential for the production of cellular energy. Ubiquinone is anaturally occurring hydrogen carrier in the respiratory chain (coenzymeQ) and structurally, it is a 2,3-dimethoxy-5-methyl-1,4-benzoquinonewith a multiprenyl side chain, the number of isoprene units varyingdepending upon the organism from which it is derived. CoQ-10 analogsinclude reduced and semi-reduced CoQ-10 and ubiquinone derivativesdescribed, for example, in WO 8803015, the teachings of which areincorporated herein by reference.

Generally, until the present discovery, most CoQ-10 liquid deliverymethods could solubilize only up at most about 10% by weight of theCoQ-10 in the solvent. Typical solvents included oils or the CoQ-10 washeld in an aqueous suspension. Alternatively, the CoQ-10 was provided asa solid in a tablet or powder.

The present invention provides the ability to solubilize CoQ-10 andanalogs thereof in monoterpenes, as defined herein, in concentrations ofup to about 60% (weight to weight) without the need to heat thesolution. In one aspect, the monoterpene solubilizes CoQ-10 from about0.1 percent by weight to about 45 percent by weight.

In particular, the solubilization of the CoQ-10 and analogs thereof withmonoterpenes can be accomplished at ambient temperatures. In one aspect,from about 5 to about 50 percent (weight CoQ-10/weight solvent) CoQ-10can be solubilized in a monoterpene. In another aspect, from about 15 toabout 40 percent w/w can be solubilized and in still another aspect,from about 20 to about 35 percent w/w CoQ-10 can be solubilized in amonoterpene.

The phrase “sufficient quantity of a monoterpene suitable to solubilizecoenzyme Q-10” is therefore intended to mean that that amount of amonoterpene that will dissolve CoQ-10 under a given set of conditions,generally, those at ambient temperature. This determination should beunderstood by one skilled in the art and can be determined by methodsknown in the art, such as by solubility studies.

One of the particular advantages of utilizing monoterpenes incombination with CoQ-10 and analogs thereof is that the enzyme isdissolved by the monoterpene. That is, many formulations currently inthe marketplace have CoQ-10 present as a suspension; a situation wherenot all the CoQ-10 is dissolved. This reduces efficacy and thebioavailability of the CoQ-10. The present invention eliminates thisdisadvantage by solubilizing the CoQ-10 in the monoterpene.

A particular advantage in using monoterpenes is that the CoQ-10 oranalog thereof does not have to be heated to dissolve into solution.This is important so that the CoQ-10 or analog thereof does not degradeupon dissolution.

The term “monoterpene” as used herein, refers to a compound having a10-carbon skeleton with non-linear branches. A monoterpene refers to acompound with two isoprene units connected in a head-to-end manner. Theterm “monoterpene” is also intended to include “monoterpenoid”, whichrefers to a monoterpene-like substance and may be used loosely herein torefer collectively to monoterpenoid derivatives as well as monoterpenoidanalogs. Monoterpenoids can therefore include monoterpenes, alcohols,ketones, aldehydes, ethers, acids, hydrocarbons without an oxygenfunctional group, and so forth.

It is common practice to refer to certain phenolic compounds, such aseugenol, thymol and carvacrol, as monoterpenoids because their functionis essentially the same as a monoterpenoid. However, these compounds arenot technically “monoterpenoids” (or “monoterpenes”) because they arenot synthesized by the same isoprene biosynthesis pathway, but rather byproduction of phenols from tyrosine. However, common practice will befollowed herein. Suitable examples of monoterpenes include, but are notlimited to, limonene, pinene, cintronellol, terpinene, nerol, menthane,carveol, S-linalool, safrol, cinnamic acid, apiol, geraniol, thymol,citral, carvone, camphor, etc. and derivatives thereof. For informationabout the structure and synthesis of terpenes, including terpenes of theinvention, see Kirk-Othmer Encyclopedia of Chemical Technology, Mark, etal., eds., 22:709-762 3d Ed (1983), the teachings of which areincorporated herein in their entirety.

In particular, suitable limonene derivatives include perillyl alcohol,perillic acid, cis-dihydroperillic acid, trans-dihydroperillic acid,methyl esters of perillic acid, methyl esters of dihydroperillic acid,limonene-2-diol, uroterpenol, and combinations thereof.

Formulation of the CoQ-10 and analogs thereof can be accomplished bymany methods known in the art. For example, the solubilized CoQ-10 oranalog thereof can be formulated in a suspension, an emulsion, anelixir, a solution, a caplet that harbors the liquid, or in a softgelatin capsule. Often the formulation will include an acceptablecarrier, such as an oil, or other suspending agent.

Suitable carriers include but are not limited to, for example, fattyacids, esters and salts thereof, that can be derived from any source,including, without limitation, natural or synthetic oils, fats, waxes orcombinations thereof. Moreover, the fatty acids can be derived, withoutlimitation, from non-hydrogenated oils, partially hydrogenated oils,fully hydrogenated oils or combinations thereof. Non-limiting exemplarysources of fatty acids (their esters and salts) include seed oil, fishor marine oil, canola oil, vegetable oil, safflower oil, sunflower oil,nasturtium seed oil, mustard seed oil, olive oil, sesame oil, soybeanoil, corn oil, peanut oil, cottonseed oil, rice bran oil, babassu nutoil, palm oil, low erucic rapeseed oil, palm kernel oil, lupin oil,coconut oil, flaxseed oil, evening primrose oil, jojoba, tallow, beeftallow, butter, chicken fat, lard, dairy butterfat, shea butter orcombinations thereof.

Specific non-limiting exemplary fish or marine oil sources includeshellfish oil, tuna oil, mackerel oil, salmon oil, menhaden, anchovy,herring, trout, sardines or combinations thereof. In particular, thesource of the fatty acids is fish or marine oil (DHA or EPA), soybeanoil or flaxseed oil. Alternatively or in combination with one of theabove identified carrier, beeswax can be used as a suitable carrier, aswell as suspending agents such as silica (silicon dioxide).

The formulations of the invention are considered dietary supplementsuseful to the increase the amounts of CoQ-10 and analogs thereof in theindividuals in need thereof.

Alternatively, the formulations of the invention are also considered tobe nutraceuticals. The term “nutraceutical” is recognized in the art andis intended to describe specific chemical compounds found in foods thatmay prevent disease. CoQ-10 or an analog thereof are such compounds.

The formulations of the invention can further include variousingredients to help stabilize, or help promote the bioavailability ofthe CoQ-10 and analogs thereof, or serve as additional nutrients to anindividual's diet. Suitable additives can include vitamins andbiologically-acceptable minerals. Non-limiting examples of vitaminsinclude vitamin A, B vitamins, vitamin C, vitamin D, vitamin E, vitaminK and folic acid. Non-limiting examples of minerals include iron,calcium, magnesium, potassium, copper, chromium, zinc, molybdenum,iodine, boron, selenium, manganese, derivatives thereof or combinationsthereof. These vitamins and minerals may be from any source orcombination of sources, without limitation. Non-limiting exemplary Bvitamins include, without limitation, thiamine, niacinamide, pyridoxine,riboflavin, cyanocobalamin, biotin, pantothenic acid or combinationsthereof.

Vitamin(s), if present, are present in the composition of the inventionin an amount ranging from about 5 mg to about 500 mg. More particularly,the vitamin(s) is present in an amount ranging from about 10 mg to about400 mg. Even more specifically, the vitamin(s) is present from about 250mg to about 400 mg. Most specifically, the vitamin(s) is present in anamount ranging from about 10 mg to about 50 mg. For example, B vitaminsare in usually incorporated in the range of about 1 milligram to about10 milligrams, i.e., from about 3 micrograms to about 50 micrograms ofB12. Folic acid, for example, is generally incorporated in a range ofabout 50 to about 400 micrograms, biotin is generally incorporated in arange of about 25 to about 700 micrograms and cyanocobalamin isincorporated in a range of about 3 micrograms to about 50 micrograms.

Mineral(s), if present, are present in the composition of the inventionin an amount ranging from about 25 mg to about 1000 mg. Moreparticularly, the mineral(s) are present in the composition ranging fromabout 25 mg to about 500 mg. Even more particularly, the mineral(s) arepresent in the composition in an amount ranging from about 100 mg toabout 600 mg.

Various additives can be incorporated into the present compositions.Optional additives of the present composition include, withoutlimitation, phospholipids, L-carnitine, starches, sugars, fats,antioxidants, amino acids, proteins, flavorings, coloring agents,hydrolyzed starch(es) and derivatives thereof or combinations thereof.

As used herein, the term “phospholipid” is recognized in the art, andrefers to phosphatidyl glycerol, phosphatidyl inositol, phosphatidylserine, phosphatidyl choline, phosphatidyl ethanolamine, as well asphosphatidic acids, ceramides, cerebrosides, sphingomyelins andcardiolipins.

L-carnitine is recognized in the art and facilitates transport ofmaterials through the mitochondrial membrane. L-carnitine is anessential fatty acid metabolism cofactor that helps to move fatty acidsto the mitochondria from the cytoplasm. This is an important factor asthis is where CoQ-10 uptake occurs.

In one aspect of the present invention, L-carnitine is included in softgel formulations in combination with CoQ-10 or an analog thereof.Suitable ratios of L-carnitine and CoQ-10 are known in the art andinclude those described in U.S. Pat. No. 4,599,232, issued to Sigma TauIndustrie Faramaceutiche Riunite S.p.A. on Jul. 8, 1986, the teachingsof which are incorporated herein in their entirety. In particular,combinations of limonene, CoQ-10 and L-carnitine in soft gelformulations are of importance. The present invention provides theadvantage of solvating large amounts (relative to that of current stateof the art) of CoQ-10 in limonene in a soft gel capsule along with anadditive, such as L-carnitine.

As used herein, the term “antioxidant” is recognized in the art andrefers to synthetic or natural substances that prevent or delay theoxidative deterioration of a compound. Exemplary antioxidants includetocopherols, flavonoids, catechins, superoxide dismutase, lecithin,gamma oryzanol; vitamins, such as vitamins A, C (ascorbic acid) and Eand beta-carotene; natural components such as camosol, carnosic acid androsmanol found in rosemary and hawthorn extract, proanthocyanidins suchas those found in grapeseed or pine bark extract, and green tea extract.

The term “flavonoid” as used herein is recognized in the art and isintended to include those plant pigments found in many foods that arethought to help protect the body from cancer. These include, forexample, epi-gallo catechin gallate (EGCG), epi-gallo catechin (EGC) andepi-catechin (EC).

The phrase “solubilized CoQ-10 and analogs thereof” is intended to meanthat the coenzyme Q-10 is solvated by the lipophilic materialsincorporated into the soft gel capsule. Typical capsules that containCoQ-10 or an analog thereof include the coenzyme or analog as a drypowder or as a suspension of crystals. It is believed that the powder orcrystallinity of the coenzyme does not facilitate absorption by thecells. The present invention overcomes this disadvantage by providingformulations wherein the coenzyme is not in a powdered or crystallineform. Microscopic evaluations of the lipophilic formulations do not showcrystals of the coenzyme. Consequently, it is believed that the solvatedcoenzyme can more easily pass into cells. This is highly advantageous indelivering increased amounts of the coenzyme into an individual'sphysiological make up.

Any dosage form, and combinations thereof, are contemplated by thepresent invention. Examples of such dosage forms include, withoutlimitation, chewable tablets, elixirs, liquids, solutions, suspensions,emulsions, capsules, soft gelatin capsules, hard gelatin capsules,caplets, lozenges, chewable lozenges, suppositories, creams, topicals,ingestibles, injectables, infusions, health bars, confections, animalfeeds, cereals, cereal coatings, and combinations thereof. Thepreparation of the above dosage forms are well known to persons ofordinary skill in the art.

For example, health bars can be prepared, without limitation, by mixingthe formulation plus excipients (e.g., binders, fillers, flavors,colors, etc.) to a plastic mass consistency. The mass is then eitherextended or molded to form “candy bar” shapes that are then dried orallowed to solidify to form the final product.

Soft gel or soft gelatin capsules can be prepared, for example, withoutlimitation, by dispersing the formulation in an appropriate vehicle(e.g. rice bran oil, monoterpene and/or beeswax) to form a highviscosity mixture. This mixture is then encapsulated with a gelatinbased film using technology and machinery known to those in the soft gelindustry. The industrial units so formed are then dried to constantweight. Typically, the weight of the capsule is between about 100 toabout 2500 milligrams and in particular weigh between about 1500 andabout 1900 milligrams, and more specifically can weigh between about1500 and about 2000 milligrams.

For example, when preparing soft gelatin shells, the shell can includebetween about 20 to 70 percent gelatin, generally a plasticizer andabout 5 to about 60% by weight sorbitol. The filling of the soft gelatincapsule is liquid (principally limonene, in combination with rice branoil and/or beeswax if desired) and can include, apart form theantioxidant actives, a hydrophilic matrix. The hydrophilic matrix, ifpresent, is a polyethylene glycol having an average molecular weight offrom about 200 to 1000. Further ingredients are optionally thickeningagents. In one embodiment, the hydrophilic matrix includes polyethyleneglycol having an average molecular weight of from about 200 to 1000, 5to 15% glycerol, and 5 to 15% by weight of water. The polyethyleneglycol can also be mixed with propylene glycol and/or propylenecarbonate.

In another embodiment, the soft gel capsule is prepared from gelatin,glycerine, water and various additives. Typically, the percentage (byweight) of the gelatin is between about 30 and about 50 weight percent,in particular between about 35 and about weight percent and morespecifically about 42 weight percent. The formulation includes betweenabout 15 and about 25 weight percent glycerine, more particularlybetween about 17 and about 23 weight percent and more specifically about20 weight percent glycerine.

The remaining portion of the capsule is typically water. The amountvaries from between about 25 weigh percent and about 40 weight percent,more particularly between about 30 and about 35 weight percent, and morespecifically about 35 weight percent. The remainder of the capsule canvary, generally, between about 2 and about 10 weight percent composed ofa flavoring agent(s), sugar, coloring agent(s), etc. or combinationthereof. After the capsule is processed, the water content of the finalcapsule is often between about 5 and about 10 weight percent, moreparticularly 7 and about 12 weight percent, and more specificallybetween about 9 and about 10 weight percent.

As for the manufacturing, it is contemplated that standard soft shellgelatin capsule manufacturing techniques can be used to prepare thesoft-shell product. Examples of useful manufacturing techniques are theplate process, the rotary die process pioneered by R. P. Scherer, theprocess using the Norton capsule machine, and the Accogel machine andprocess developed by Lederle. Each of these processes are maturetechnologies and are all widely available to any one wishing to preparesoft gelatin capsules.

Typically, when a soft gel capsule is prepared, the total weight isbetween about 250 milligrams and about 2.5 gram in weight, e.g., 400-750milligrams. Therefore, the total weight of additives, such as vitaminsand antioxidants, is between about 80 milligrams and about 2000milligrams, alternatively, between about 100 milligrams and about 1500milligrams, and in particular between about 120 milligrams and about1200 milligrams.

For example, a soft gel capsule can be prepared by mixing a 35% solutionof CoQ-10 and limonene (w/w) (e.g., 104 milligrams of CoQ-10 in 193.14milligrams of limonene) with between about 0.01 grams and about 0.4grams (e.g., 0.1 grams) tocopherol, between about 200 grams and about250 grams (e.g., 225 grams) rice bran oil and between about 0.01 gramsand about 0.5 grams betacarotene (e.g. about 0.02 grams). The mixture isthen combined with encapsulated within a gelatin capsule as describedabove.

The present invention also provides packaged formulations of amonoterpene with CoQ-10 and instructions for use of the tablet, capsule,elixir, etc. Typically, the packaged formulation, in whatever form, isadministered to an individual in need thereof that requires and increasein the amount of CoQ-10 in the individual's diet. Typically, the dosagerequirements is between about 1 to about 4 dosages a day.

CoQ-10 has been implicated in various biochemical pathways and issuitable for the treatment of cardiovascular conditions, such as thoseassociated with, for example, statin drugs that effect the body'sability to produce CoQ-10 naturally. CoQ-10 has also been implicated invarious periodontal diseases. Furthermore, CoQ-10 has been implicated inmitochondrial related diseases and disorders, such as the inability toproduct acetyl coenzyme A, neurological disorders, for example, such asParkinson's disease and, Prater-Willey syndrome.

The following examples are intended to be illustrative only and shouldnot be considered limiting.

EXAMPLES

Formulations of CoQ-10 can be prepared in the following ratios by mixingthe components together and then placing into a soft gel capsule.

Component Example 1 Example 2 CoQ-10 104.09 mg 104.09 mg MixedTocopherols 269.03 mg 269.03 mg (372 IU/g) Rice Bran Oil 176.02 mg —Natural Beta Carotene  10.05 mg  10.05 mg (20% by weight) Yellow Beeswax 20.0 mg — D-limonene — 196.02 mg Total weight   580 mg   580 mg

Example 2 demonstrates that the use of limonene solubilizes CoQ-10without the requirement of beeswax and/or rice bran oil being present.Examples 1 and 2 can be incorporated into soft gel capsules by standardmethods known in the art.

Component Example 3 Example 4 CoQ-10 17.95 g 17.95 g EPAX 2050TG 48.77 g45.49 g D-Limonene 35.70 g 35.70 g 5-67 Tocopherol —  0.86 g (1000 IU/g)

Examples 3 and 4 demonstrate that CoQ-10 can be solubilized in scalablequantities. Additives, such as EPAX 2050 TG (an ω-3 oil; 20% EPA/50% DHAas triglycerides, remainder fatty acid/triglycerides; Pronova Biocare)and tocopherols (5-67 Tocopherol; BD Industries) can easily beincorporated into such limonene containing formulations. The resultantmixtures contained approximately 100 mg of CoQ-10 per soft gel capsule.Preparation of the soft gel capsules was accomplished by methods wellknown in the art.

Component Example 5 Example 6 CoQ-10 (98%) 62.45 mg 62.45 mg  Vitamin Emixed tocopherols 69.19 mg 161.3. mg   (700 mg/g) D-Limonene 118.1 mgnone Soybean oil 30.26 mg none 5-67 Tocopherol  60.0 mg none (1000 IU/g)yellow beeswax none 15.0 mg Rice bran oil none 188.71 mg  Natural betaCarotene none 7.54 mg mg/capsule mg/capsule

Examples 5 and 6 provide a comparison between soft gel capsules preparedwith D-limonene and without D-limonene and enzyme CoQ-10. Examples 5 and6 will be referred to throughout the following paragraphs to showefficacy in delivery with the use of the monoterpene, D-limonene.

The single 60 mg dose peak absorption characteristics and the 28-day 60mg daily dose steady state bioavailability of the solubilized CoQ₁₀formulation was determined in five (5) normal male (N=3) and female(N=2) volunteers. The peak absorption study was done over 12 hours. Forthe control sample, the volunteers were in a rested and fastedcondition-minimum eight (8) hours. Serial blood samples were taken at 0,4, 6, 8, and 12 hours after ingesting 60 mg of a softgel product (eithersolubilized CoQ₁₀ (Example 5) or Example 6, a non-solubilized CoQ₁₀formulation. In the steady state bioavailability study, daily doses of60 mg of the solubilized CoQ₁₀ formulation were taken with breakfast.CoQ₁₀ in plasma was measured using the hexane extraction and HPLCdetection method described in “A New Method to Determine the Level ofCoenzyme Q10 in One Drop of Human Blood for Biomedical Research”, ManabuMorita and Karl Folkers, Biochem. Biophys. Res. Commun. 191(3), 950-954,1993, the contents of which are incorporated herein in their entirety.The solubilized CoQ₁₀ formulation was a soft gel capsule that contained60 mg CoQ₁₀, 118.1 mg limonene, 30.26 mg soybean oil and vitamin E asdescribed in Example 5. The non-solubilized formulation was a soft gelcapsule that contained 60 mg CoQ₁₀, 188.71 mg rice bran oil, 161.3 mgvitamin E (and additional additives) as described in Example 6.

Group mean control plasma CoQ₁₀ level (0.88±0.13 μg/ml) was in thenormal range. Tmax after ingestion of a single 60 mg capsule was in six(6) hours and the mean peak plasma level (Cmax) was 2.28±0.14 μg/ml. Theamount of solubilized CoQ₁₀ absorbed at Cmax was 4,765.51±825.39 μg or7.96±1.38% of the ingested dose. With daily dosing the plasmasolubilized CoQ₁₀ level increased to a mean plateau level of 2.68±0.15μg/ml in 14 days and remained fairly constant thereafter. The 28-dayplasma level was 2.75±0.22 μg/ml. The solubilized CoQ₁₀ bioavailabilityin plasma was 6,498.90±1,634.76 μg, and the area under the plasma timebase curve was 42.27±2.29 μg/ml·day. These data demonstrate that thesolubilized CoQ₁₀ formulation was absorbed significantly (p<0.001). Thepeak absorption of 7.96% of the ingested dose and the steady statebioavailability after 28 days was significantly (p<0.01) greater thanthat found in Example 6.

The solubilized CoQ₁₀ formulation (Example 5) absorption is greater thanthat of most softgel CoQ₁₀ products in which CoQ₁₀ crystals aresuspended in a lipid base and those products that provide only a driedpowder composition.

Peak Absorption Characteristics and Steady State Bioavailability ofSolubilized CoQ₁₀ formulation

The use of Coenzyme Q₁₀ (CoQ₁₀) around the world has surpassed theproduction capabilities of the Japanese producers. CoQ₁₀ is also rapidlyentering the clinical consumer market with the positive study reports onheart failure, Parkinson's disease, muscular ataxias, low energy geneticsyndromes, statin drug inhibition of CoQ₁₀ synthesis and recentpublications that show that CoQ₁₀ and its precursors in the body inhibitfarensyl-transferase and thus turn off the growth and rapid division ofcancer cells. With these advances in CoQ₁₀ research and the conclusionsthat plasma CoQ₁₀ levels for clinical efficacy should be raised to about3.2 μg/ml, more companies have been seeking to develop CoQ₁₀ productswith improved absorption and steady state bioavailability. Theabsorption of CoQ₁₀ is not the same for all CoQ₁₀ products found in themarket place. In general dry powder delivery systems have 0.5 to 2% peakabsorption. Dry powder CoQ₁₀ in a lipid base that is incorporated intosoft gelatin capsules has better peak absorption (2.0-3.0%). Thisappears to be dependant on the number and size of the CoQ₁₀ crystals inthe product.

The following data relate to peak absorption characteristics of a single60 mg dose and the steady state bioavailability of a daily 60 mg dosefor the solubilized CoQ₁₀ softgel formulation. Both studies wereconducted on the same five (5) normal volunteer subjects. Peakabsorption and steady state bioavailability characteristics werecompared to that of Example 6 which was collected using a similar studydesign but different volunteers.

Methods

Five normal volunteers (3 males/2 females) were randomly selected from ascreened group of 15 individuals (Table I). The exclusion criteriawere: 1) smoker, 2) individual taking a CoQ₁₀ product, 3) individualwith high plasma cholesterol, 4) individual taking drugs known tointerfere with endogenous synthesis or CoQ₁₀ absorption, 5) individualon vegetarian diet, and 6) athlete.

TABLE I Physical Characteristics of Study Volunteers PLASMA AGE HEIGHTWEIGHT VOLUME VOLUNTEER YEARS SEX INCHES POUNDS MILLILITERS PDOB 01 43 F63.50 147.00 3139.00 RFRE 02 42 M 66.25 170.75 3720.00 AJOH 03 43 M69.50 205.00 3928.00 SHAL 04 26 M 70.50 192.50 3870.00 NJOH 05 39 F63.75 126.00 2520.00

After being fully familiarized with the experimental design and theirresponsibilities, the volunteers had their questions answered by theprinciple investigator, and read and signed a volunteer consent form. Onday 0 of the study, volunteers reported to the testing facility at 0600in a rested and fasted state-minimum eight (8) hours. Vital signs weretaken, an intercath was placed in a forearm vein, and a control bloodsample was collected for determining the control CoQ₁₀ plasma level. Thevolunteers were then given a single 60 mg dose of the solubilized CoQ₁₀formulation. This was followed by a breakfast consisting of orange juiceor milk (2%) with a bagel or cereal. Blood samples were drawn again athours 4, 6, 8 and 12; vital signs and safety data were collectedsimultaneously. Starting with day 1 of the study, the volunteers took 60mg of solubilized CoQ₁₀ formulation daily for the next 28 days. Duringthis time, volunteers followed their regular diet and activity schedulesand returned to the testing facility on days 7, 14, 21, and 28 at 0600in a rested and fasted condition—minimum eight (8) hours—for the purposeof collecting vital signs and safety data, and to have a venous bloodsample collected from which plasma CoQ₁₀ levels were determined.

All CoQ₁₀ samples were collected in vaccutainers containing EDTA toprevent clotting. The samples were cooled in ice water and thencentrifuged to separate the plasma from the formed elements. The plasmawas pipetted into a sealable transfer container, labeled according tovolunteer identification and hour of collection and frozen at −20°centigrade. All plasma samples were shipped overnight in dry ice to anindependent laboratory for CoQ₁₀ analysis. The method used was that asdescribed in Morita & Folkers (supra) hexane extraction and HPLCdetection.

Individual volunteer data points were entered into a Microsoft Excelspreadsheet. Descriptive statistics were used to calculate group meansSD and SE. Statistical differences between group control and each groupsample for the peak absorption and the steady state weekly levels weredetermined using a standard t-test for differences between group means.A probability of p≤0.05 was accepted as significant.

Results

I: Peak Absorption Study

Individual and group means±SE & SD descriptive statistics data for the60 mg single dose peak absorption study are presented in Table II andthe individual data plotted on a 12 hour time base are shown in FIG. 1.Control plasma CoQ₁₀ was variable between volunteers (range=0.77-1.09μg/ml). The group means±SD was 0.88±0.13 μg/ml. This is considered to bein the normal range. Within four hours after ingesting the solubilizedCoQ₁₀ the plasma levels for the group increased significantly (p≤0.01)to 1.36±0.12 μg/ml. Peak plasma levels occurred at six (6) hours (Tmax)and the maximum plasma concentration (Cmax) was 2.28±0.14 μg/ml.Thereafter plasma CoQ₁₀ rapidly decreased over the next two hours to amean level of 1.58±0.23 μg/ml during the rapid tissue uptake period ofCoQ₁₀. The peak absorption kinetics calculated from the peak absorptiondata are presented in Table IV.

TABLE II Individual and Group Solubilized CoQ₁₀ formulation: Single Dose(60 mg) Peak Absorption Study Sample Time (Hours) 0 4 6 8 12 Volunteer 10.77 1.35 2.09 1.30 1.10 2 1.09 1.56 2.40 1.60 1.46 3 0.92 1.36 2.391.90 1.76 4 0.79 1.24 2.16 1.42 1.27 5 0.85 1.28 2.34 1.67 1.45 Mean0.88 1.36 2.28 1.58 1.41 Standard Error 0.06 0.06 0.06 0.10 0.11Standard 0.13 0.12 0.14 0.23 0.25 Deviation P-value 3.24E−05 1.57E−060.000766 0.002338

The amount of CoQ₁₀ absorbed at Cmax was 4,769.51±825.39 μg. Whencompared to the ingested dose (60,000 μg), the percent of the doseabsorbed at Cmax was 7.95±1.38%. In the first two hours after Cmax anaverage of 2196.14±523.83 μg was distributed out of the blood and intothe body cells. The amount was 46.46±9.85% of that absorbed at Cmax.

II: Steady State Plasma CoQ₁₀ Bioavailability

Individual and group means±SD descriptive statistics data for the 28-day60 mg/day steady state plasma CoQ₁₀ bioavailability for the solubilizedCoQ₁₀ formulation are presented in Table III and graphically in FIGS. 2and 4. Again there was a variation between volunteers. In seven (7) daysthe basal plasma CoQ₁₀ level increased significantly (p≤0.01) to2.39±0.13 μg/ml. Plasma levels plateaued for each volunteer between the7th and 14th day and remained fairly constant thereafter (FIG. 2). Atthe 28th day the group means plasma CoQ₁₀ level was 2.75±0.22 μg/ml(p≤0.001). The calculated steady state increase in plasma CoQ₁₀ was6,458.90±1,634.76 μg at a constant daily dose of 60 mg/day (Table V). Ina steady state condition the group mean relative increase in plasmaCoQ₁₀ was 314.42±39.07%. The area under the plasma CoQ₁₀ and time basecurve between days 0 and 28 days (AUC_(0-28day))(AUC denotes area underthe curve) is used to equate the CoQ₁₀ bioavailability. The AUC for thisproduct was 42.27±2.29 μg/ml·day.

TABLE III Individual and Group Solubilized CoQ₁₀: Steady State (60mg/day) Plasma CoQ10 Bioavailability Study Time (Days) AUC (0-28 0 7 1421 28 % Change day) ug/ml · day Volunteer 1 0.77 2.20 2.48 2.56 2.67285.71 42.77 2 1.09 2.30 2.79 2.80 2.78 211.01 38.68 3 0.92 2.52 2.783.00 3.10 273.91 42.22 4 0.79 2.42 2.78 2.70 2.68 306.33 42.61 5 0.852.49 2.56 2.60 2.50 292.94 45.05 Mean 0.88 2.39 2.68 2.73 2.75 314.4242.27 Standard Error 0.06 0.06 0.07 0.08 0.10 17.47 1.02 StandardDeviation 0.13 0.13 0.15 0.18 0.22 39.07 2.29 p-value 2.65E−05 3.11E−065.13E−06 5.13E−06

TABLE IV Individual and Group Single Dose Peak AbsorptionCharacteristics for Solubilized CoQ₁₀ formulation Control Change PlasmaPlasma Plasma Change in Rapid Q10 Amt. Q10 % Distributed Q10 Cmax Q10Plasma Plasma % of Dose Distribution Distributed of Amt. ug/ml ug/mlug/ml Vol ml Q10 ug Absorbed ug/ml ug Absorbed Volunteer 1 0.77 2.091.32 3139.00 4143.48 6.91 0.61 1914.79 46.21 2 1.09 2.40 1.31 3720.004873.20 8.12 0.80 2976.00 61.07 3 0.92 2.39 1.47 3928.00 5774.16 9.620.49 1924.72 33.33 4 0.79 2.16 1.37 3870.00 5301.90 8.84 0.64 2476.8046.72 5 0.85 2.34 1.49 2520.00 3754.80 6.26 0.67 1688.40 44.97 Mean 0.882.28 1.48 3435.40 4769.51 7.95 0.64 2196.14 46.46 SD 0.06 0.06 0.08268.17 369.12 0.62 0.05 234.26 4.41 SE 0.13 0.14 1.39 599.65 825.39 1.380.11 523.83 9.85

III: Particle and Crystalline Characteristics of Solubilized CoQ₁₀

Photomicrographs of solubilized CoQ₁₀ (Example 5) and Example 6 showedthat Example 6 had many small crystals of CoQ₁₀, whereas the solubilizedCoQ₁₀ (Example 5) showed no crystals, and appeared to be a homogenousdistribution of CoQ₁₀ molecules in solution.

DISCUSSION

The study determined the peak single dose (60 mg) absorptioncharacteristics and the steady state plasma CoQ₁₀ bioavailability inresponse to a constant daily dose of 60 mg/day for 28 days ofsolubilized CoQ₁₀. The control plasma CoQ₁₀ data for the small group(N=5) was in the normal range (Tables 1 &2). The plasma CoQ₁₀ increaseat Cmax (2.28±0.14 μg/ml) was significantly (p<0.001) above the controllevel as was the amount of CoQ₁₀ added to the plasma at Cmax (Table IVand V).

TABLE V Individual and Group Solubilized CoQ₁₀ (Example 5): Steady State(60 mg/day) CoQ₁₀ Bioavailability Study Plasma Q C-CoQ10 28 Day ChangePlasma Vol Change AUC (0-28 day) ug/ml ug/ml ug/ml ml ug/ml % Changeug/ml · day Volunteer 1 0.77 2.67 1.90 3,139.00 5,964.10 346.75 42.77 21.09 2.78 1.69 3,720.00 6,286.80 255.05 38.68 3 0.92 3.10 2.18 3,928.008,563.04 336.96 42.22 4 0.79 2.68 1.89 3,870.00 7,314.30 339.24 42.61 50.85 2.50 1.65 2,525.00 4,166.25 294.12 45.05 Mean 0.88 2.75 1.863,436.40 6,458.90 314.42 42.27 Standard 0.06 0.10 0.09 267.32 731.0917.47 1.02 Error Standard 0.13 0.22 0.21 597.75 1,634.76 39.07 2.29Deviation

Peak absorption and steady state bioavailability data were comparedbetween the solubilized CoQ₁₀ (Example 5) and Example 6. Comparisonswere made by examining FIGS. 3 and 4. These Figures show the peakabsorption curves (FIG. 3) and the steady state bioavailability curves(FIG. 4) characteristics of both the solubilized CoQ₁₀ and CoQ_(10sol)products plotted on the same time base. Cmax for Example 6 with a 30 mgdose increased 0.53±0.28 μg/ml above the control level. With this changein plasma CoQ₁₀ 1813.33±96.65 μg of CoQ₁₀ was added to the blood atCmax. The calculated percent (%) of ingested dose absorbed was6.04±0.32%. This is significantly less than the 1.48±0.39 ug/ml changein plasma CoQ₁₀ and the 7.95±1.38% of the 60 mg ingested dose of thesolubilized CoQ₁₀ formulation. Thus, the relative increases in the peakplasma CoQ₁₀ at Cmax, the amount of CoQ₁₀ absorbed at Cmax and thepercent of ingested dose absorbed at Cmax between the solubilized CoQ₁₀(Example 5) and Example 6 formulations were 80, 60 and 40 percentgreater respectively for the solubilized CoQ₁₀ formulation. These datashow that Example 6 at a dose of 30 mg is significantly (p<0.01) lessabsorbed than 60 mg of solubilized CoQ₁₀ formulation. The steady statebioavailability of Example 6 is also significantly less than that ofsolubilized CoQ₁₀ formulation as shown in FIG. 4.

At 28 days with a 60 mg daily dose, Example 6 resulted in a group meansteady state plasma CoQ₁₀ level of 2.26±0.74 μg/ml. This issignificantly (p≤0.01) less than the 2.75±0.22 μg/ml measured for thesolubilized CoQ₁₀ formulation using the same 60 mg/day dose. Similarly,the AUCo-28 day for the solubilized CoQ₁₀, CoQ₁₀ was significantlygreater (p≤0.01) than that found for Example 6 (42.27±2.29-vs.-29.6±4.61μg/ml/day). These data comparisons also show that the solubilized CoQ₁₀formulation CoQ₁₀ bioavailability is significantly greater than that ofExample 6.

Not to be limited by theory, as to why the solubilized CoQ₁₀ formulation(Example 5) has better absorption than Example 6 may be explained by thephysical characteristics of the two formulations. Both Example 6 and thesolubilized CoQ₁₀ formulations were made by the same soft gelencapsulating process. The ingredients in the two formulations weredifferent relative to the lipid carrier molecules (Rice bran oil inExample 6 and Soybean oil and D-Limonene oil in the solubilized CoQ₁₀formulation (Example 5)). On examination of the two formulations, thecontents of both were an oily matrix. The solubilized CoQ₁₀ formulationappeared to be more liquid (less solids) than Example 6. Example 6 wasreddish brown in color due to the beta-carotene. The solubilized CoQ₁₀formulation was dark brown in color. Upon microscopic examinationExample 6 was found to have small crystals, whereas the solubilizedCoQ₁₀ was devoid of crystals. It is postulated that the solubilizedCoQ₁₀ formulation consists of a larger fraction of single CoQ₁₀molecules and exerts a greater osmotic concentration of CoQ₁₀ outsidethe intestinal cells, thus a greater driving force for the facilitateddiffusion process for CoQ₁₀ absorption.

Since the CoQ₁₀ crystal has a melting point 10° centigrade above bodytemperature (37° C.) and completely melt to single molecules at 65°centigrade, it is believed that the lower absorption of Example 6 is dueto the larger proportion of CoQ₁₀ crystals in solution and thephysiological fact that the body cannot absorb a crystal. Only singlemolecules in water or lipid solution can be absorbed across theintestinal mucosal membrane or transported across any epithelial cellmembrane.

In summary, the solubilized CoQ₁₀ formulation peak absorption kineticsand steady state bioavailability is significantly greater than that ofExample 6. The 7.95% absorption of the ingested dose makes this asuperior composition to provide increased amounts of CoQ₁₀ to a subjectin need thereof.

Although the present invention has been described with reference topreferred embodiments, persons skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

All literature and patent references cited throughout the applicationare incorporated by reference into the application for all purposes.

What is claimed is:
 1. A solubilized composition comprising: a) coenzymeQ-10 or an analog thereof; b) a sufficient quantity of d-limonene or aderivative thereof suitable to solubilize said coenzyme Q-10 or analogthereof and keep it solubilized at ambient temperature: and c) anacceptable carrier, wherein between about 5 percent and about 12 percentof the coenzyme Q-10 in said composition is absorbed into the bloodstream of a healthy human.
 2. The composition of claim 1, wherein saidcoenzyme Q-10 or an analog thereof is selected from the group consistingof coenzyme Q-10, reduced coenzyme Q-10 and semi-reduced coenzyme Q-10.3. The composition of claim 1, wherein said limonene derivative isselected from the group consisting of perillyl alcohol, perillic acid,cis-dihydroperillic acid, trans-dihydroperillic acid, a methyl ester ofperillic acid, a methyl ester of dihydroperillic acid, limonene-2-diol,uroterpenol, and a combination thereof.
 4. The composition of claim 1,wherein said composition is in the form of a solution, an elixir, asuspension, or a capsule.
 5. The composition of claim 4, wherein saidcapsule is a soft gelatin capsule.
 6. The composition of claim 5,wherein said carrier is soybean oil.
 7. A solubilized coenzyme Q-10composition comprising: a) coenzyme Q-10 or an analog thereof; b) asufficient quantity of d-limonene or a derivative thereof suitable tosolubilize said coenzyme Q-10 or analog thereof; and c) an acceptablecarrier, wherein said composition provides a steady state plasma levelconcentration of between about 2.5 μg/ml to about 3.5 μg/ml of coenzymeQ-10 or analog thereof.
 8. The composition of claim 7, wherein saidcoenzyme Q-10 or an analog thereof is selected from the group consistingof coenzyme Q-10, reduced coenzyme Q-10 and semi-reduced coenzyme Q-10.9. The composition of claim 7, wherein said limonene derivative isselected from the group consisting of perillyl alcohol, perillic acid,cis-dihydroperillic acid, trans-dihydroperillic acid, a methyl ester ofperillic acid, a methyl ester of dihydroperillic acid, limonene-2-diol,uroterpenol, and a combination thereof.
 10. The composition of claim 7,wherein said composition is in the form of a solution, an elixir, asuspension, or a capsule.
 11. The composition of claim 10, wherein saidcapsule is a soft gelatin capsule.
 12. The composition of claim 11,wherein said carrier is soybean oil.
 13. A solubilized coenzyme Q-10composition comprising: a) coenzyme Q-10 or an analog thereof; b) asufficient quantity of d-limonene or a derivative thereof suitable tosolubilize said coenzyme Q-10 or analog thereof; and c) an acceptablecarrier, wherein said composition provides a peak plasma level ofbetween about 2.1 μg/ml to about 3.0 μg/ml of coenzyme Q-10 or analogthereof.
 14. The composition of claim 13, wherein said coenzyme Q-10 oran analog thereof is selected from the group consisting of coenzymeQ-10, reduced coenzyme Q-10 and semi-reduced coenzyme Q-10.
 15. Thecomposition of claim 13, wherein said limonene derivative is selectedfrom the group consisting of perillyl alcohol, perillic acid,cis-dihydroperillic acid, trans-dihydroperillic acid, a methyl ester ofperillic acid, a methyl ester of dihydroperillic acid, limonene-2-diol,uroterpenol, and a combination thereof.
 16. The composition of claim 13,wherein said composition is in the form of a solution, an elixir, asuspension, or a capsule.
 17. The composition of claim 16, wherein saidcapsule is a soft gelatin capsule.
 18. The composition of claim 1,wherein the composition further includes an additional antioxidant. 19.The composition of claim 18, wherein the additional antioxidant istocopherol.